Highly sensitive and selective detection of steroid hormones using

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Highly sensitive and selective detection of steroid hormones using terahertz molecule-specific sensors Sang-Hun Lee, Donggeun Lee, Man Ho Choi, Joo-Hiuk Son, and Minah Seo Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.9b01066 • Publication Date (Web): 30 Apr 2019 Downloaded from http://pubs.acs.org on April 30, 2019

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Analytical Chemistry

Highly sensitive and selective detection of steroid hormones using terahertz molecule-specific sensors

Sang-Hun Lee,1 Donggeun Lee,1 Man Ho Choi,2 Joo-Hiuk Son,3 and Minah Seo*,1,4

1Sensor

System Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea

2Molecular

Recognition Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea

3Department

of Physics, University of Seoul, Seoul 02504, Republic of Korea

4Division

of Nano & Information Technology, KIST School, Korea University of Science and Technology (UST), Seoul 02792, Republic of Korea

*[email protected]

ABSTRACT Discrimination and quantification of trace amounts of steroid hormones in biological specimens are needed to elucidate their expression changed because their biological functions are responsible for the development and prevention of endocrine disorders. Although mass spectrometry-based assays are most commonly recommended, it has been still issued to develop a new type of highly sensitive and selective detection methods in clinical practices. Here, we introduce a label-free type of terahertz molecule sensor capable of sensing and identification of progesterone and 17α-OH-progesterone selectively. Nano-slot array based sensing chips were used as launching pads for absorption cross-section enhancement of molecules at a reliable terahertz frequency. Using nano-slots with resonances at 1.17 THz corresponding to intrinsic THz absorption resonance mode for progesterone and 1.51 THz corresponding to it for 17α-OH-progesterone respectively, each steroid shows prominent transmittance change in terms of its amount. In particular, the sensing performance has been much improved by controlling evaporation speed, in turn, resulting in a homogeneous distribution of the molecules onto sensing hot spot efficiently.

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INTRODUCTION Steroid hormones are composed of three cyclohexane and one cyclopentane rings to yield the completely hydrogenated chemical structures. Depending on various functional groups attaching to the rings as a core structure, there are many steroids with different biochemical functions that can be classified as sex steroids, progestogens, and corticoids, which are metabolized from cholesterol. The selective detection and discrimination of steroids are quite challenging due to their structural similarity and conjugation diversity. Thus far, the steroids and their metabolites in a biological specimen have been intensively studied using mass spectrometry combined with chromatographic separation.1 Although the mass spectrometry-based techniques provide both quantitative and qualitative information with hundreds of steroids and appropriate sensitivity responding to concentration levels in human blood, they require complex and labor-intensive sample preparation steps.2 As other widely-applied methods in steroid sensing, either antibody or aptamer-based sensing techniques such as radioimmunoassay and enzyme-linked immunosorbent assay (ELISA), and synthetic receptor for fluorescence response show sufficient analytical sensitivity,3 however, the cross-reactivity should be considered at low level quantification.4 In recent decades, THz time-domain spectroscopy (TDS) has been widely applied to such research branches as medical diagnosis and pharmaceutics.5–7 It is due to that the THz-TDS technique has many advantages such as low photon energy under tens of meV that does not disturb chemical bonding, sensitive interaction to molecular behaviors such as vibration, torsion and libration, and sufficiently high signal-to-noise ratio with broad-band spectrum in a single measurement.8,9 Based on these advantages, THz techniques have shown potential application including diagnostic in vivo imaging and spectroscopy for characterization of a biomolecule, even in a very similar structure.10 In previous studies, it was reported that several steroid hormones have resonance features in the THz region by cryogenic experiments and molecular simulation for comprehending their resonance nature.11–13 Despite its similar molecular structure, steroid hormones show distinguishable THz fingerprints among them. However, it is still hindered to detect and investigate each steroid hormone sample selectively in low concentration using typical THz systems, because of its low absorption resulting from concentration in organs. In order to overcome such low absorption cross-section at the THz regime, metamaterial-based sensing chip can be proposed. The sensing devices can improve not only sensitivity assisted by enhancing light-matter interaction, but also selectivity by resonance frequency fitting to that of the target analyte by modifying its geometry.14–16 Thus the THz metamaterial sensor has recently been demonstrated as a promising technique to sensitive detecting of biochemical including proteins,17–19 nucleotides,20 pharmaceuticals,21 and microorganisms.22 There are also several recent works on detection of chemicals, biomarkers, or cells in solution by combining THz resonator patterns and microfluidic channels to overcome the potential limitation of THz-TDS with losing of


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signals due to huge water absorption.23,24 Here, we demonstrate a highly sensitive and selective THz sensing method combined with electric field enhancement by the nano-slot structured sensing array for discrimination and quantification of steroid hormones. The THz molecule sensing method, which utilizes absorption enhancement induced by the nano-slot, provides sufficient sensitivity, as well proved by recent earlier works.17,20 The nano-slot, which is a sub-wavelength structure of extremely narrow metal gap of λ/10 - λ/10,000, induces electric field enhancement in the order of hundreds times, in contrast with a relatively constant magnetic field of only a few times.25–27 This asymmetric amplification ratio between electric- and magnetic-fields leads to enormous enlargement of molecular absorption cross-section that can be used for sensitive molecular detection beyond the typical sensitivity of the THz spectrometer.28 We designed nano-slot arrays for two resonance frequencies, targeting to absorption resonances of several steroids. As the most notable and important steroids related to pathophysiological issues on congenital adrenal hyperplasia (CAH) and female reproductive biology, progesterone and 17α-hydroxyprogesterone (17α-OH-progesterone) were considered for this study. Both progesterone and 17α-OH-progesterone have characteristic resonance features in reliable THz regime.13 The sensing chip, thus, was designed to selectively and efficiently detect their absorption features. We monitored the THz transmission change of the steroids on the nano-slot sensing chips. It was noted that control of drying temperature is very crucial to place the steroids into the sensing surface, where the THz field is dominantly localized. Thus the evaporation environment was cautiously controlled during the experiments.

EXPERIMENTAL SECTION Steroid sensing using THz nano-slot The sensing mechanism is based on magnifying of absorption cross-section in accordance with the THz field enhancement by nano-slot antenna resonances as described in Figure 1a. The THz wave funneling through the slot has an intense amplitude, which leads to sensitivity enhancement in the near-field region. Thus more molecules of steroids should be placed near the slot for more THz signal change. We considered four steroid hormones of progesterone, 17α-OH-progesterone, cortisol and cortisone with liquid drop-and-dry method onto the nano-slot sensing chip as seen in Figure 1b. The molecular structures for steroid hormones are very similar based on the identical molecular skeleton with different functional groups depicted with red lines. All samples were purchased from Sigma-Aldrich Co. Due to low water solubility, the steroids were dissolved in 10 mg/ml in methanol, then diluted in DI-water in appropriate concentrations. The steroid solution of 1.5 μl was drop-casted onto the sensing surface of the nano-slot array for fully covering the patterned area. After the solution was completely evaporated, THz transmission spectra were measured. In order to detect target molecules sensitively and selectively,



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the optimization of the nano-slot design is essential. Thus we investigated the absorption spectra of the steroids for determination the target absorption frequency. Steroid samples in a very high concentration of more than 99% were firstly investigated in a pellet form (500 μm in thickness) to acquire THz absorption spectra. The absorption coefficient, α, can be derived from the relation between incident (E0) 1

1

and transmitted THz waves (Epellet) as follow: α(ω) = ― 𝑑ln (𝑇𝑝𝑒𝑙𝑙𝑒𝑡(𝜔)) = ― 𝑑ln

(|

𝐸𝑝𝑒𝑙𝑙𝑒𝑡(𝜔) 2 𝐸0(𝜔)

| ), where

d is the thickness of the pellet. Absorption resonances of four steroids are shown in Figure 1c. Steroids show quite different resonant absorption features in spite of their structural similarity. Especially progesterone and 17α-OH-progesterone have a remarkable spectral feature with absorption resonance. The absorption resonances near 1.2 THz of progesterone and 1.5 THz of 17α-OH-progesterone are dominantly distinguishable magnitude comparing to other steroids. These spectra have good agreement with the previous report, which explained the origin of the molecular vibrational signatures from experiments with thick and high-density tablet steroid samples comparing to density functional theory calculation:13 the prominent resonances of progesterone and 17α-OH-progesterone are mainly from libration mode near 1.2 THz and bending mode near 1.5 THz, respectively. We utilized these absorption fingerprints of 1.2 THz and 1.5 THz for specifying the correspond steroids. Unlike these steroids, cortisone and cortisol do not show distinctive absorption resonance. Although cortisone and cortisol have similar absorption spectra in the spectral range, higher absorption coefficient can be seen for cortisone above 1.3 THz than cortisol. This absorption difference might be exploited for classification these steroids. In this study, however, for the clear demonstration of selective and sensitive THz detection between different steroids, we choose progesterone and 17α-OH-progesterone as target hormones.


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Figure 1. (a) Schematic of steroids sensing using THz nano-slot sensing chip, which magnifies the absorption cross-section of molecules near the slot. (b) Chemical structures of four steroid hormones and the experimental procedure. (c) THz absorption spectra of steroid hormones in pellet types and (d) transmission spectra of nano-slot arrays, targeted to 1.17 THz for progesterone and 1.51 THz for 17αOH-progesterone.

Fabrication of a nano-slot array We chose two main molecular absorption resonances in THz spectra of Figure 1c; a resonance of 1.2 THz for progesterone and resonance of 1.5 THz for 17α-OH-progesterone. For these frequencies, two types of nano-slot patterns were designed. The resonance wavelength of the nano-slot can be determined approximately using following relation: 𝑓𝑟𝑒𝑠 = 𝑐0/𝐿 2(𝑛2 + 1), where fres is the resonance frequency, c0 is the speed of light, L is the slot length, and n is the refractive index of the substrate.29 The transmission spectra of the nano-slot arrays are shown in Figure 1d. The spectra are normalized to maximum transmittance at the resonance frequency. The nano-slot arrays show a clear resonance feature at their resonance frequency, which is well matched to absorption resonance of steroid samples. In detailed, slots have the width of w=500 nm, and the length of L=50.0 μm and 37.6 μm for resonances at 1.17 THz and 1.51 THz, respectively, as seen in Figure 2a. Narrower slot width allows higher sensitivity, but the injected amount of sample might be limited. Because there is a clear trade-off between the sensitivity of the sensing chip and the total volume of the injected sample, the width of w=500 nm was properly chosen after such parameters optimized. To cover sufficiently the THz beam



spot, two nano-slot arrays covering an area of 2 mm x 2 mm were fabricated with identical slots. The slots are separated by Sx=40 μm and Sy=10 μm in the transverse and longitudinal direction, respectively, to suppress the Rayleigh minima in the measurement range.30 The slot arrays were patterned using photolithography on the gold film of 150 nm thickness, which is thicker than skin-depth of 80 nm at 1 THz for regarding as perfect electric conductor. The slot pattern was fabricated on the high resistivity silicon wafer (>10,000 Ωcm, 675 μm thickness), which has a very low absorption coefficient and constant refractive index in the THz region.

Experimental setup for THz spectroscopy The experiments were conducted with common THz-time domain spectroscopy (TDS) system as seen in Figure 2b. The system is driven by Ti:sapphire femtosecond laser of 800 nm of the center wavelength, 100 fs of the pulse width and 80 MHz of the repetition rate. The laser beam is split into two parts by the beam splitter: THz emission using the photoconductive antenna and detection by electro-optic sampling with ZnTe crystal, which system can obtain transmission spectra from 0.1 THz to 2 THz with high signal-to-noise ratio up to 70 dB. Pairs of off-axis parabolic mirror and TPX (polymethylpentene) lens are used for collimating and focusing the THz wave generated from the photoconductive antenna. The THz system is enclosed with purged air of relative humidity under 1% to avoid unwanted absorption by water vapor. The THz electric field was acquired by the Fourier transform of the waveform in timedomain, which is scanned using optical sampling method. The transmittance is defined as T(ω)=|Esample(ω)/E0(ω)|2, where Esample and E0 are transmitted electric fields through the sample and a bare substrate, respectively.


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Figure 2. (a) Structure of the nano-slot array. (b) Scheme of the experimental setup for THz-TDS.

RESULTS AND DISCUSSION Sensitivity difference by sample evaporation condition For optical sensing using metamaterial sensing chips, drop-casting method is usually applied for a dissolved sample in a liquid solvent. Such drop-and-dry, however, can sometimes bother the interpretation of sensing result, since the casted molecules are inhomogeneously dispersed onto the sensing chip. In the previous study, Y. Li et al. reported that nano-particle suspended solution with the drop-and-dry method can have a different surface profile by controlling of evaporation condition.31 Fast evaporation under higher temperature can make more homogeneous surface than slow evaporation under room-temperature. According to the different interfacial energy between substrates and dropped solutes, the evaporation condition should be carefully considered. Thus, we treated the nano-slot array sensing chip under different evaporated condition. The progesterone solution of 6 μg/ml (9 ng) was drop-casted onto the sensing surface of the nano-slot array and evaporated under high temperature, 50℃ (fast evaporation) and room-temperature, 20℃ (slow evaporation). Under fast evaporation condition, the stain of the solution was widely spread on the sensing surface, while steroid molecules were concentrated at a very tiny spot under slow evaporation, as shown in the optical microscopy images of Figure 3a (schematic Figure 3c) and Figure 3b (schematic Figure 3d), respectively. The microscopy images were contrast-enhanced under the same condition to make the figures clear. We monitored THz



transmission changes depending on the amount of sample and evaporation condition as seen in Figure 3d. It seems that the lower limit of measurement is about 6 ng under slow evaporation because there is no distinguishable transmission change below the limit. It can be explained with the assumption that most of the dropped steroid molecules were much localized at certain chip area of the tiny dark spot in Figure 3b, thus most of the nano-slots cannot contain the samples inside the sensing hot-spot. This localization of molecular stain in the spot is occurred by Cassie-Baxter wetting, because of more hydrophobic sensing surface than bare Si wafer.31–33 On the other hand, noticeable transmission change in terms of the amount of the sample can be appeared in the whole measured range under fast evaporation. This fast evaporation technique was applied for all further experiments.

Figure 3. (a, b) Microscopy images of nano-slot arrays with sample evaporation (progesterone, 9 ng). The images were contrast-enhanced to represent progesterone samples more clearly (dark area here). The sample under fast evaporation condition was widely spread out as thin-film form unlike the sample under slow evaporation condition that was strongly concentrated at a very tiny spot. (c-d) Scheme of steroid distributions resulting from different evaporation environment (e) Transmission difference at resonance frequency by the quantity of progesterone and evaporation condition.


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THz spectroscopy with nano-slot Based on the condition of high evaporation rate, which makes more sensitive transmittance change, progesterone and 17α-OH-progesterone of various quantities were examined with the nano-slot sensing chips for two resonance frequencies at 1.17 THz and 1.51 THz, as shown in Figure 4a-d. Each THz spectrum shows a distinct resonance behavior at the intended single frequency according to the length of the nano-slots. For all measurements, steroid deposition induces transmittance decrement. Especially each steroid shows more transmittance decreasing at their target frequency as intended in Figure 1c and d, respectively. On the other hand, there are not noticeable resonance frequency shifts comparing to the bare nano-slot. The resonance shift of the nano-slot with a specific length is generally occurred by the effective refractive index of surrounding materials. It seems that the amount of steroid samples in the experimental range is too low to change the effective refractive index of surroundings. Thus, we focused on the transmittance change with ignoring resonance shift. Maximum transmission changes at each resonance frequency are summarized in Figure 4e and f. In the measurement range under 9 ng of steroids, transmittances of both sensing chip are monotonically changed. Progesterone and 17α-OH-progesterone show remarkable transmission change on their targeted frequencies of 1.17 THz and 1.51 THz, respectively, comparing to off-resonance frequency. In this measurement, the amount of the steroid is related to the thickness of the target sample on the sensing surface of the slot array. It is known that the molecular absorption cross-section for THz waves is highly enhanced at the slot surface.28,34 It is, therefore, deduced that transmission saturation is occurred by increasing the sample thickness, which is thicker than the field-enhanced area of THz waves.35 Due to such trend of transmission change, all data 𝑥𝑛

were fitted by a sigmoidal function of Hill equation, y = 𝑉𝑚𝑎𝑥𝑘𝑛 + 𝑥𝑛, where Vmax is maximum transmittance change, k is the amount of steroid for half-maximum transmittance and n is the rapidity for a transmission change. The points with faint color were handled as outliers on the fitting processes. Progesterone shows noticeable transmission difference at 1.17 THz, which is target resonance for progesterone, as seen in Figure 4e. On the other hand, 17α-OH-progesterone shows only a few percent in transmission change, since it does not have a distinct absorption feature at this frequency (1.17 THz). In stark contrast, in Figure 4f, 17α-OH-progesterone shows drastically changed transmittance and saturation behavior above 3 ng on the nano-slot sensing chip of 1.51 THz resonance, which comes from huge absorption at the matched frequency.



Figure 4. Transmission spectra of nano-slot arrays with steroid hormones: Progesterone (a, b) and 17αOH-progesterone (c, d) are dropped on the sensing surface of the nano-slot arrays of 1.17 THz (a, c) and 1.51 THz (b, d) resonances. The insets show magnified view of the rectangles near resonance peaks. Summary of transmission change by two steroids on the nano-slot arrays of 1.17 THz (e) and 1.51 THz (f) resonances, which are designed for selective sensing progesterone and 17α-OH-progesterone, respectively.


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These transmission changes by steroid molecules are directly comparable to absorption coefficients at corresponding frequencies as shown in Figure 5. Transmission changes (red, left axis) are for 9 ng of steroids, which is assumed as an almost saturated regime for all sensor and sample combinations. Absorption coefficients (blue, right axis) at the corresponding resonance frequency are extracted from the measured THz spectra in Figure 1c. Transmission changes show quite good correlation with absorption coefficients. Based on this relation, progesterone and 17α-OH-progesterone can be distinguished by comparing transmission difference at two different nano-slot sensing chips. In our measurements, we examined steroid of a nano-gram level using THz sensing chips, which include thousand identical slots inside the square array region (1645 slots for 1.17 THz resonance chip and 2075 slots for 1.51 THz resonance chip). Because the slots are operated independently without resonance coupling by sufficient separation, amount of steroid interacting with each slot can be considered. Due to the geometry of Figure 2a, the open ratio in a slot period is approximately 1%. In conclusion, steroids of only tens of femtograms can participate in THz transmission change inside a slot.

Figure 5. THz transmission changes by steroids of 9 ng (left axis, red) and absorption coefficients of the samples (right axis, blue) at the resonance frequency of each sensing chip.

CONCLUSION In conclusion, we demonstrate highly sensitive and selective THz detection for steroid hormones in very low quantity. Nano-slot based THz sensor was used to acquire transmission change at the target frequency, combining with the THz-TDS technique. To increase interaction between nano-slots and steroid molecules, drop-casted hormone solution is deposited under rapid evaporation condition. Homogeneous molecular distribution by fast evaporation boosts the THz transmittance change than evaporation under room-temperature. Based on the sensitivity-boosting deposition condition, two types of the nano-slot array are examined to quantitatively distinguish progesterone and 17α-OH-



progesterone. the target frequency for chemical sensing was determined based on THz absorption spectra of steroids: 1.17 THz for progesterone and 1.51 THz for 17α-OH-progesterone. On the nanoslot at 1.17 THz, progesterone shows prominent transmittance change corresponding to its THz absorption resonance. Meanwhile, at 1.51 THz, weak transmission change was measured due to resonance mismatching between the progesterone sample and the nano-slot. Another target sample, 17α-OH-progesterone, shows also a distinguishable difference on the matched frequency of 1.51 THz than at 1.17 THz where the sample does not have absorption resonance. Using these transmission differences between on- and off- the absorption resonance, biomolecules with a similar structure can be sensitively distinguished. Finally, this study will be a cornerstone for the development of fast and convenient detection technology in clinical practices.

ACKNOWLEDGEMENT This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2019M3A6B3030638) and KIST intramural grants (2E29490, 2E29290, and 2V06780).

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